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Description of key information

In a Hazelton Laboratories, 1968 study, DIDP was administered to four groups of 10 male and 10 female rats in dietary levels of 0.05%, 0.3% and 1% (approximately 25, 150 and 500 mg/kg/d, respectively). A group of untreated rats served as control. No compound-related effects were observed at any dietary levels with regard to physical appearance, behavior or survival. Growth of the test rats was not significantly affected. Body weight gains for the two highest levels in males were lower than controls (but not significantly different) and the two test groups were comparable through the ninth week. Overall, weight gains at 13 weeks for the male test groups showed a dose-related, although slight, decrease. Body weight gains for the high dose females were only slightly lower than the controls. Food consumption values were comparable to the controls. The clinical laboratory values for the test groups showed no significant compound-related differences from control values.
Observations at necropsy revealed the livers of the high dose group animals, particularly the males, to be markedly larger than those of the control rats. Statistical analysis revealed the liver weights and liver/body weight ratios for the high dose group males and females to be significantly higher than those for the corresponding controls. No other consistent gross changes were noted in the liver. Histologically, the liver showed no compound-induced alterations. The kidney/body weight ratios but not the absolute weights in the high and intermediate dose group males were significantly higher than those for the corresponding controls. Histologically, the kidneys showed no compound-induced alterations.
A minimal increase in thyroid activity was observed at the highest dose. It can be concluded from this study that the NOAEL is 0.3% (about 150 mg/kg/d) based on the fact that the highest dose leads to liver and thyroid effects. Relative (but not absolute) kidney weights were affected at this intermediate ...

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
150 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
500 mg/m³

Additional information

Oral: The target organ for oral sub-acute and sub-chronic DIDP toxicity in animals (rodent and dog) appears to be the liver (increased liver weights and significant changes in liver peroxisomal enzyme activities in rodents). It is clear that NOAELs derived from rat studies are related to peroxisome proliferation-mediated liver effects, which are considered to be species specific. Humans are less sensitive than rats.  The overall NOAEL for systemic effects following oral exposure in rats was 150 mg/kg/d.

Inhalation: Repeated (two weeks) exposure to DIDP aerosol at concentrations approximating 500 mg/m3 produced local irritation but no systemic toxicity in rats.  Accordingly the systemic no effect level exceeded 0.5 mg/l.

In a 2-week study (General Motors Research Laboratories, 1981) designed to evaluate the fate of DIDP (see Section 5.1), toxicity was assessed. DIDP was administered to 8 male rats (6 for control) by inhalation (aerosol) at analytical concentration of 505±7 mg/m3(MMAD: 0.98 μm) 6 hours a day, 5 times per week. Rats were observed daily for body weight gain, appearance and gross behavior. Animals were sacrificed at the end of the observation period (3 weeks) and tissue samples taken for histopathology. There were no marked outward signs of toxicity during exposure. The rate of body weight gain was not different between control and exposed animals. Effects in the lungs were: moderate increase in the width of alveolar septa with slight interstitial mixed inflammatory reactions, alveolar macrophages and type II pneumocytes were increased in number, peribronchial lymphoid tissue appeared slightly more prominent. In liver, spleen and kidneys, no obvious histologic alterations were noted except for a slight hepatic fatty metamorphosis. No systemic toxicity, but local irritant effects were observed at the concentration tested, thus a NOAEL of 0.5 mg/l (500 mg/m3) can be assumed.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification